Reduced levels of endogenous steroid hormones in humans often lead to a variety of undesirable clinical symptoms. For example, low testosterone levels in men (hypogonadism) may result in clinical symptoms including impotence, lack of sex drive, muscle weakness, and osteoporosis. Similarly, in women, reduced levels of testosterone and/or estrogen may result in female sexual disorder, which include clinical symptoms such as lack of sex drive, lack of arousal or pleasure, decreased energy levels or fatigue with blunted motivation, flat mood or depression, reduced sense of well-being, insomnia, irritability, partial decreases in vaginal lubrication, and osteoporosis. Moreover, reduced levels of estrogen and/or progesterone in women, such as that caused by menopause, often result in clinical symptoms including hot flashes, night sweats, vaginal atrophy, decreased libido, and osteoporosis.
The hormone testosterone (T) has historically been thought of as a male hormone, but it is also synthesized in women in small amounts, primarily by the ovaries and adrenal glands. The physiological functions ascribed to testosterone in women include: development of pubic and axillary hair as well as emerging sexual libido; anabolic effect on bone density and muscle tone; sexual libido; and overall vitality and sense of psychological well-being. Testosterone plasma concentrations in pre-menopausal women fluctuate during the menstrual cycle, with the total T plasma concentrations generally ranging between 15-65 ng/dL, but in the years leading to postmenopausal transition, levels of circulating androgens begin to decline as a result of age-related reductions of both ovarian and adrenal secretion. Generally, women with androgen deficiency have total T levels of less than 20-25 ng/dL, while oophorectomized women can have total T levels of less than 10 ng/dL. Thus, the goals of testosterone therapy are to restore plasma T levels so they approximate the premenopausal state and to alleviate the symptoms of Hypoactive Sexual Desire Disorder (HSDD) associated with T deficiency.
Currently, there are no testosterone products approved in the U.S. for treatment of HSDD in women. One transdermal testosterone matrix patch has been submitted for NDA approval for the treatment of HSDD, and Estratest™, an oral preparation containing methyltestosterone in combination with esterified estrogen, is approved for treatment of moderate-to-severe vasomotor symptoms associated with menopause, but not for HSDD.
Further, although steroid hormone concentrations may be restored to normal or near-normal levels by hormone replacement therapy, the current forms of treatment (i.e., oral, intramuscular, subcutaneous, transdermal patches and topical formulations) have several disadvantages.
For example, orally administered testosterone is largely degraded in the liver, and is therefore not a viable option for hormone replacement since it does not allow testosterone to reach systemic circulation. Further, analogues of testosterone modified to reduce degradation (e.g., methyltestosterone and methandrostenolone) have been associated with abnormalities in liver function, such as elevation of liver enzymes and conjugated bilirubin. Injected testosterone produces wide peak-to-trough variations in testosterone concentrations that do not mimic the normal fluctuations of testosterone, and makes maintenance of physiological levels in the plasma difficult. Testosterone injections are also associated with mood swings and increased serum lipid levels. Injections require large needles for intramuscular delivery, which leads to diminished patient compliance due to discomfort.
To overcome these problems, transdermal delivery approaches have been developed to achieve therapeutic effects in a more patient friendly manner. For example, U.S. Pat. No. 5,460,820 discloses a testosterone-delivering patch for delivering 50 to 500 μg/day of testosterone to a woman. In addition, U.S. Pat. No. 5,152,997 discloses a device comprising a reservoir of testosterone with a skin permeation enhancer and a means for maintaining the reservoir in diffusional communication with the skin, such as an adhesive carrier device or a basal adhesive layer. A transdermal patch or such other adhesive device, however, still presents disadvantages such as user discomfort, skin irritation due to the adhesive required to secure the patch to a pat of the user's body, and also the discomfort due to removal of the patch, during which both the user's skin and hair can be pulled.
The present invention addresses the problems associated with the known hormone replacement therapy by providing testosterone in a gel form for transdermal and/or transmucosal delivery. In this regard, an adhesive patch is not needed to administer the drug. Rather, the medicament is simply dispensed from a container and applied to an area of the skin. Accordingly, the present invention eliminates the discomforts caused by the conventional patch device.
Another significant advantage of the present invention is that since the user can simply apply the gel onto their skin, there is no application of an unsightly patch. Accordingly, the user can apply the gel to an area of skin that is visible to others. As the gel is absorbed into the skin, its “invisibility” provides a significant improvement over the conventional obstructive transdermal products which require external, non-discreet means of securing the product to the user. Thus, the present transdermal and/or transmucosal delivery of testosterone advantageously provides a convenient, pain-free, and non-invasive method of administering testosterone to a subject in need thereof.
Although administration of drugs in a gel form is favorable to users due to its pain-free and discreet administration, it has a drawback of difficulty in dispensing the proper dosage for administration. For example, it is known to provide medicaments in the form of gels, ointments, or lotions, in a tube, similar to the type of tube used to store toothpaste. Typically, the user is directed to squeeze the tube to dispense the ointment or gel containing the drug in a specific amount, such as an inch on a finger tip, or some other type of length. This is problematic especially because it requires careful dispensing of the medicament, and precise measuring on the part of the user to ensure administration of the proper dosage. Oftentimes users over- or under-dose themselves due to carelessness or simply because it is difficult to measure the amount of medicament dispensed from the particular tube. Accordingly, administering an accurate dosage amount of a gel-type medicament from such containers is difficult, and usually only a ballpark measure can be dispensed.
Thus, a method and system for administering gel-type medicaments in a precise, metered amount is desired. The present invention meets this need by providing a gel-like medicament in combination with a metered dosage device. The metered dosage device dispenses an amount of medicament that corresponds to a particular dosage. Accordingly, active agents in a gel-like form can be applied in the desired dosage for effective treatment.